Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions

Ingvild Løberg Tangen, Henrica M J Werner, Anna Berg, Mari K. Halle, Kanthida Kusonmano, Jone Trovik, Erling A. Hoivik, Gordon Mills, Camilla Krakstad, Helga B. Salvesen

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Objective In endometrial cancer loss of progesterone receptor (PR, gene name PGR) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities. Methods 686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray. Results PR protein level was significantly associated with PGR mRNA expression (P < 0.001) and patient survival (P < 0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR. Conclusion Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.

Original languageEnglish (US)
Pages (from-to)3003-3010
Number of pages8
JournalEuropean Journal of Cancer
Volume50
Issue number17
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Progesterone Receptors
Endometrial Neoplasms
Oligonucleotide Array Sequence Analysis
Disease Progression
Neoplasms
Protein Array Analysis
Messenger RNA
Survival
Estrogen Receptors
Names
Cell Cycle
Proteins
Therapeutics
Immunohistochemistry
Clinical Trials
Neoplasm Metastasis
Gene Expression
Pharmaceutical Preparations
Genes

Keywords

  • CDK inhibitors
  • Endometrial cancer
  • Progesterone receptor
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tangen, I. L., Werner, H. M. J., Berg, A., Halle, M. K., Kusonmano, K., Trovik, J., ... Salvesen, H. B. (2014). Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions. European Journal of Cancer, 50(17), 3003-3010. https://doi.org/10.1016/j.ejca.2014.09.003

Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions. / Tangen, Ingvild Løberg; Werner, Henrica M J; Berg, Anna; Halle, Mari K.; Kusonmano, Kanthida; Trovik, Jone; Hoivik, Erling A.; Mills, Gordon; Krakstad, Camilla; Salvesen, Helga B.

In: European Journal of Cancer, Vol. 50, No. 17, 01.01.2014, p. 3003-3010.

Research output: Contribution to journalArticle

Tangen, IL, Werner, HMJ, Berg, A, Halle, MK, Kusonmano, K, Trovik, J, Hoivik, EA, Mills, G, Krakstad, C & Salvesen, HB 2014, 'Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions', European Journal of Cancer, vol. 50, no. 17, pp. 3003-3010. https://doi.org/10.1016/j.ejca.2014.09.003
Tangen, Ingvild Løberg ; Werner, Henrica M J ; Berg, Anna ; Halle, Mari K. ; Kusonmano, Kanthida ; Trovik, Jone ; Hoivik, Erling A. ; Mills, Gordon ; Krakstad, Camilla ; Salvesen, Helga B. / Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions. In: European Journal of Cancer. 2014 ; Vol. 50, No. 17. pp. 3003-3010.
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abstract = "Objective In endometrial cancer loss of progesterone receptor (PR, gene name PGR) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities. Methods 686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray. Results PR protein level was significantly associated with PGR mRNA expression (P < 0.001) and patient survival (P < 0.001). Loss of PR increased with disease progression, with 23{\%} of the primary tumours and 76{\%} of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR. Conclusion Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.",
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AU - Werner, Henrica M J

AU - Berg, Anna

AU - Halle, Mari K.

AU - Kusonmano, Kanthida

AU - Trovik, Jone

AU - Hoivik, Erling A.

AU - Mills, Gordon

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AU - Salvesen, Helga B.

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N2 - Objective In endometrial cancer loss of progesterone receptor (PR, gene name PGR) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities. Methods 686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray. Results PR protein level was significantly associated with PGR mRNA expression (P < 0.001) and patient survival (P < 0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR. Conclusion Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.

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